DeGeneres also got candid about something that deeply influenced her early on in life, when she was just 20 years old: Her girlfriend at the time was killed in a fatal car accident.

“I was living with her, and when she was killed, I couldn’t afford to live where we were living together,” she said. “So I moved into this tiny little basement apartment that I was sleeping on a mattress on the floor infested with fleas. I thought, ‘Why is this beautiful 21-year-old girl gone and fleas are here?’ And I just thought it would be amazing if we could pick up the phone and call up God and ask questions and actually get an answer.”

She continued to face various struggles in her personal life as she became an increasingly visible force in the comedy world.

“I was by myself,” she said of touring as a stand-up. “It’s not like I had friends I could afford to put up with me. I wasn’t flying private. I was flying commercial all the time and changing planes. I hate flying. I get anxiety when I fly so I couldn’t wait to stop touring.”

And then there's DeGeneres' decision to come out to the public. When she finally opted to do so, she was hit with a flurry of backlash, which sent her into a downward spiral of depression.

Add to that the fact that her show, "Ellen," was canceled a year after her character came out on TV.

"Everybody assumed I was just nonstop talking about it," DeGeneres said. "It hurt my feelings. I was getting jokes made at my expense on every late-night show, people were making fun of me. I was really depressed. And because of that, and because the show was canceled, I was looked at as a failure in this business. No one would touch me. I had no agent, no possibility of a job, I had nothing."

Twenty years later, DeGeneres said she is “grateful” for her life experiences, which have led her to her success today.

“I can't believe that I was able to achieve what I achieved, lose it all and then get to this point in my life at 60 years old,” she said. “To start over at 45. Nobody starts over in this business at 45, much less a woman. I'm really grateful that I had that experience and it made me a stronger person."

DeGeneres married wife Portia de Rossi in August 2008, a momentous occasion that makes the talk show host “really proud.”

“The fact that that was never talked about on television, but it's becoming part of the vernacular that someone can hear ‘wife,’” DeGeneres said. “At least it's digesting slowly into society and that I can talk about my amazing, incredible life with another woman is doing something."